scholarly journals Behavioral and Neurostructural changes associated with Chronic Amygdala Hyperactivation

2021 ◽  
Author(s):  
Keith A Misquitta ◽  
Sierra A Codeluppi ◽  
Jaime K Knoch ◽  
Yashika Bansal ◽  
Toshi Tomoda ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Basolateral Amygdala ◽  
Ex Vivo ◽  
Critical Role ◽  
Progressive Increase ◽  
Causal Link ◽  
Activity Level ◽  
Designer Drug ◽  
Psychiatric Illnesses ◽  
Density Analysis

Background: The amygdala (AMY) is a key brain region of the limbic system that plays a critical role in emotion processing and stress response. Functional magnetic resonance imaging (fMRI) studies identified abnormal AMY activation in psychiatric illnesses including major depressive disorder (MDD). Stress exposure is a major precipitating factor of MDD episodes which are associated with AMY hyperactivity. Preclinical studies using of pharmacologic, opto- and chemogenetic approaches to activate AMY neurons have consistently demonstrated that acute AMY hyperactivation induces anxiety-like behaviors in mice. However, it remains unknown if chronic hyperactivation of the amygdala (cHOA) is sufficient to induce chronic stress-like deficits or is a susceptibility factor for chronic stress-induced behavioral, volumetric and synaptic deficits. Methods: Using designer receptor exclusively activated by designer drug (DREADD) approach, basolateral amygdala (BLA) neurons of Camk2a-cre mice infected with a virus driving the expression of the Gq-coupled DREADD were activated with clozapine-N-oxide (in drink water for 5 weeks). Mice were then exposed to chronic restraint stress (CRS; 1X/day for 1hr) for 2 weeks. All mice were behaviorally assessed in the Phenotyper (PT), and sucrose consumption tests (SCT) each week and in the novelty supressed feeding (NSF, once at the end of the experiment). Animals were then perfused for ex vivo-MRI and puncta density analysis. Results: We found that mice with cHOA displayed a progressive increase in baseline anxiety-like deficits in the PT test and slightly more marked deficits following CRS compared to controls, but not statistically different from animals subjected to CRS alone. Also, cHOA did not exacerbate CRS effect in the NSF. No significant cAH effect was found in the SCT before or after CRS. MRI analysis revealed no statistical charges between groups, while increased synaptic puncta density was found in cHOA mice subjected to CRS compared to cHOA or CRS alone. Conclusion: We demonstrate that cAH is sufficient to induce anxiety and may exacerbate CRS effects on anxiety and synaptic measures. Results also suggest that cHOA was not sufficient to induce depressive-like behavior and was not a vulnerability factor for stress-induced depressive-like behavior in mice. Altogether, our findings imply that a strong causal link between AMY hyperactivity and elevated anxiety, but not depressive-like behaviors and provide critical information to clinical research focused on using AMY activity level as a biomarker in stress-related illnesses.

scholarly journals HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Peng Zhong ◽  
Casey R Vickstrom ◽  
Xiaojie Liu ◽  
Ying Hu ◽  
Laikang Yu ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Chronic Stress ◽  
Ex Vivo ◽  
Critical Role ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Hcn Channels ◽  
Neuron Firing ◽  
Ventral Tegmental

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

2019 ◽  
Vol 133 (22) ◽  
pp. 2283-2299
Author(s):  
Apabrita Ayan Das ◽  
Devasmita Chakravarty ◽  
Debmalya Bhunia ◽  
Surajit Ghosh ◽  
Prakash C. Mandal ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Chronic Inflammation ◽  
Ex Vivo ◽  
Human Subjects ◽  
Critical Role ◽  
Atherosclerotic Cardiovascular Disease ◽  
Tnf Α ◽  
Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2

2008 ◽  
Vol 294 (6) ◽  
pp. C1521-C1530 ◽  
Author(s):  
Shuji Kondo ◽  
Yixin Tang ◽  
Elizabeth A. Scheef ◽  
Nader Sheibani ◽  
Christine M. Sorenson
Keyword(s):  
Cell Migration ◽  
Vascular System ◽  
Ex Vivo ◽  
Vascular Development ◽  
Critical Role ◽  
Endothelial Cell Migration ◽  
Cellular Functions ◽  
Capillary Morphogenesis ◽  
Angiogenesis Assay ◽  
Ischemic Retinopathy

Apoptosis plays a critical role during development and in the maintenance of the vascular system. B-cell leukemia lymphoma 2 (bcl-2) protects endothelial cells (EC) from apoptosis in response to a variety of stimuli. Previous work from this laboratory demonstrated attenuation of postnatal retinal vascular development and retinal neovascularization during oxygen-induced ischemic retinopathy in bcl-2-deficient (bcl-2−/−) mice. To gain further insight into the function of bcl-2 in the endothelium, we isolated retinal EC from bcl-2+/+ and bcl-2−/− mice. Retinal EC lacking bcl-2 demonstrated reduced cell migration, tenascin-C expression, and adhesion to vitronectin and fibronectin. The bcl-2−/− retinal EC also failed to undergo capillary morphogenesis in Matrigel. In addition, using an ex vivo angiogenesis assay, we observed reduced sprouting from aortic rings grown in culture from bcl-2−/− mice compared with bcl-2+/+ mice. Furthermore, reexpression of bcl-2 was sufficient to restore migration and capillary morphogenesis defects observed in bcl-2−/− retinal EC. Mechanistically, bcl-2−/− cells expressed significantly less endothelial nitric oxide synthase, an important downstream effecter of proangiogenic signaling. This may be attributed to increased oxidative stress in the absence of bcl-2. In fact, incubation of retinal EC or aortic rings from bcl-2−/− mice with the antioxidant N-acetylcysteine rescued their capillary morphogenesis and sprouting defects. Thus, bcl-2-mediated cellular functions play important roles not only in survival but also in proangiogenic phenotype of EC with a significant impact on vascular development and angiogenesis.

scholarly journals Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

2021 ◽  
Author(s):  
Pantelis Antonoudiou ◽  
Phillip LW Colmers ◽  
Najah L Walton ◽  
Grant L Weiss ◽  
Anne C Smith ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Post Partum ◽  
Critical Role ◽  
Behavioral Outcomes ◽  
Theta Oscillations ◽  
Allosteric Modulators ◽  
Post Partum Depression ◽  
Antidepressant Effects ◽  
Behavioral States ◽  
Network States

AbstractBrexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAa receptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. Here, we demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), are capable of modulating oscillatory states across species, which we propose may contribute to long-lasting changes in behavioral states. We identified a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAaRs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA is sufficient to alter behavioral states and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAa receptors, a mechanism distinct from other GABAa PAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 induces long-lasting protection from chronic stress-induced disruption of network states, which correlates with improved behavioral outcomes. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

scholarly journals The Duality of Caspases in Cancer, as Told through the Fly

2021 ◽  
Vol 22 (16) ◽  
pp. 8927
Author(s):  
Caitlin Hounsell ◽  
Yun Fan
Keyword(s):  
Tumour Progression ◽  
Critical Role ◽  
Dual Role ◽  
Activity Level ◽  
Therapeutic Approaches ◽  
Cancer Treatments ◽  
Aspartic Proteases ◽  
Critical Components ◽  
Established Role

Caspases, a family of cysteine-aspartic proteases, have an established role as critical components in the activation and initiation of apoptosis. Alongside this a variety of non-apoptotic caspase functions in proliferation, differentiation, cellular plasticity and cell migration have been reported. The activity level and context are important factors in determining caspase function. As a consequence of their critical role in apoptosis and beyond, caspases are uniquely situated to have pathological roles, including in cancer. Altered caspase function is a common trait in a variety of cancers, with apoptotic evasion defined as a “hallmark of cancer”. However, the role that caspases play in cancer is much more complex, acting both to prevent and to promote tumourigenesis. This review focuses on the major findings in Drosophila on the dual role of caspases in tumourigenesis. This has major implications for cancer treatments, including chemotherapy and radiotherapy, with the activation of apoptosis being the end goal. However, such treatments may inadvertently have adverse effects on promoting tumour progression and acerbating the cancer. A comprehensive understanding of the dual role of caspases will aid in the development of successful cancer therapeutic approaches.

scholarly journals The Y14-p53 Regulatory Circuit in Megakaryocyte Differentiation and Thrombocytopenia

2020 ◽  
Author(s):  
Chun-Hao Su ◽  
Wei-Ju Liao ◽  
Wei-Chi Ke ◽  
Ruey-Bing Yang ◽  
Woan-Yuh Tarn
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Ex Vivo ◽  
Critical Role ◽  
Platelet Production ◽  
Noncoding Regions ◽  
Regulatory Circuit ◽  
Hel Cells ◽  
Absent Radius ◽  
Megakaryocyte Differentiation

SUMMARYThrombocytopenia-absent radius syndrome is caused by a deletion in chromosome 1q21.1 in trans with RBM8A mutations in the noncoding regions. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, indicating a disorder of platelet production. Rbm8aKOMK mice accumulated immature megakaryocytes in the bone marrow and spleen. Depletion of Y14/RBM8A in human erythroleukemia (HEL) cells inhibited phorbol ester-induced polyploidy and downregulated the signaling pathways associated with megakaryocyte maturation. Accordingly, Rbm8aKOMK mice had reduced expression of surface glycoproteins on platelets and impaired coagulation. Moreover, p53 level was increased in Y14-depleted HEL cells and Rbm8aKOMK megakaryocytes. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Knockout of Trp53 in part restored the platelet count of Rbm8aKOMK mice. These results indicate that the Y14-p53 circuit plays a critical role in megakaryocyte differentiation and platelet production.

scholarly journals My D88-Dependent Interplay Between Myeloid and Endothelial Cells in the Initiation and Progression of Obesity-Associated Inflammatory Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-44-SCI-44
Author(s):  
Xiaoxia Li
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Low Grade

Abstract Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. Disclosures No relevant conflicts of interest to declare.

scholarly journals Separable Dorsal Raphe Dopamine Projections Mediate Sociability and Valence

2021 ◽  
Author(s):  
Kay Tye ◽  
Gillian Matthews ◽  
Mackenzie Lemieux ◽  
Elizabeth Brewer ◽  
Raymundo Miranda ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Ex Vivo ◽  
Affective State ◽  
Well Being ◽  
Dorsal Raphe ◽  
Receptor Expression ◽  
Dopamine Neurons ◽  
Bed Nucleus ◽  
Distributed Target ◽  
Dorsal Raphé

Abstract Affiliative social connections facilitate well-being and survival in numerous species. Engaging in social interactions requires positive and negative motivational drive, elicited through coordinated activity across neural circuits. However, the identity, interconnectivity, and functional encoding of social information within these circuits remains poorly understood. Here, we focused on downstream projections of dorsal raphe nucleus (DRN) dopamine neurons (DRNDAT), which we previously implicated in ‘negative drive’-induced social motivation. We show that three prominent DRNDAT projections – to the bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and posterior basolateral amygdala (BLP) – play separable roles in behavior, despite substantial collateralization. Photoactivation of the DRNDAT-CeA projection promoted social behavior and photoactivation of the DRNDAT-BNST projection promoted exploratory behavior, while the DRNDAT-BLP projection supported place avoidance, suggesting a negative affective state. Downstream regions showed diverse, region-specific, receptor expression, poising DRNDAT neurons to act through dopamine, neuropeptide, and glutamate transmission. Furthermore, we show ex vivo that the effect of DRNDAT photostimulation on downstream neuron excitability was predicted by baseline cell properties, suggesting cell-type-specific modulation. Collectively, these data indicate that DRNDAT neurons may bias behavior via precise modulation of cellular activity in broadly-distributed target structures.

scholarly journals Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

2010 ◽  
Vol 42A (2) ◽  
pp. 103-113 ◽  
Author(s):  
Matthew S. Barnabei ◽  
Nathan J. Palpant ◽  
Joseph M. Metzger
Keyword(s):  
Cardiac Function ◽  
Genetic Divergence ◽  
Ex Vivo ◽  
Inbred Mouse ◽  
Critical Role ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Cardiac Decompensation

Inbred mouse strains play a critical role in biomedical research. Genetic homogeneity within inbred strains and their general amenability to genetic manipulation have made them an ideal resource for dissecting the physiological function(s) of individual genes. However, the inbreeding that makes inbred mice so useful also results in genetic divergence between them. This genetic divergence is often unaccounted for but may be a confounding factor when comparing studies that have utilized distinct inbred strains. Here, we compared the cardiac function of C57BL/6J mice to seven other commonly used inbred mouse strains: FVB/NJ, DBA/2J, C3H/HeJ, BALB/cJ, 129X1/SvJ, C57BL/10SnJ, and 129S1/SvImJ. The assays used to compare cardiac function were the ex vivo isolated Langendorff heart preparation and in vivo real-time hemodynamic analysis using conductance micromanometry. We report significant strain-dependent differences in cardiac function between C57BL/6J and other commonly used inbred strains. C57BL/6J maintained better cardiac function than most inbred strains after ex vivo ischemia, particularly compared with 129S1/SvImJ, 129X1/SvJ, and C57BL/10SnJ strains. However, during in vivo acute hypoxia 129X1/SvJ and 129S1/SvImJ maintained relatively normal cardiac function, whereas C57BL/6J animals showed dramatic cardiac decompensation. Additionally, C3H/HeJ showed rapid and marked cardiac decompensation in response to esmolol infusion compared with effects of other strains. These findings demonstrate the complex effects of genetic divergence between inbred strains on cardiac function. These results may help inform analysis of gene ablation or transgenic studies and further demonstrate specific quantitative traits that could be useful in discovery of genetic modifiers relevant to cardiac health and disease.

Signal transducer and activator of transcription 5a (STAT5a) is required for eosinophil differentiation of human cord blood–derived CD34+ cells

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 134-142 ◽  
Author(s):  
Miranda Buitenhuis ◽  
Belinda Baltus ◽  
Jan-Willem J. Lammers ◽  
Paul J. Coffer ◽  
Leo Koenderman
Keyword(s):  
Cord Blood ◽  
Target Genes ◽  
Ex Vivo ◽  
Critical Role ◽  
Ectopic Expression ◽  
Hematopoietic Cells ◽  
Myeloid Cell ◽  
Dominant Negative ◽  
Human Cord Blood ◽  
Cd34 Cells

Abstract Signal transducers and activators of transcription (STATs) have been reported to play a critical role in the differentiation of several myeloid cell lines, although the importance of STATs in the differentiation of primary human hematopoietic cells remains to be established. Terminal eosinophil differentiation is induced by interleukin-5 (IL-5), which has also been demonstrated to activate STAT5. We have investigated whether STAT5 plays a critical role during eosinophil differentiation using umbilical cord blood–derived CD34+ cells. In this ex vivo system, STAT5 expression and activation are high early during differentiation, and STAT5 protein expression is down-regulated during the final stages of eosinophil differentiation. Retroviral transductions were performed to ectopically express wild-type and dominant-negative STAT5a (STAT5aΔ750) in CD34+ cells. Transduction of cells with STAT5a resulted in enhanced proliferation compared with cells transduced with empty vector alone. Interestingly, ectopic expression of STAT5a also resulted in accelerated differentiation. In contrast, ectopic expression of STAT5aΔ750 resulted in a block in differentiation, whereas proliferation was also severely inhibited. Similar results were obtained with dominant-negative STAT5b. Forced expression of STAT5a enhanced expression of the STAT5 target genes Bcl-2 andp21WAF/Cip1, suggesting they may be important in STAT5a-mediated eosinophil differentiation. These results demonstrate that STAT5 plays a critical role in eosinophil differentiation of primary human hematopoietic cells.

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